Publications by authors named "Xiupeng Zhang"

56 Publications

WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression.

Cell Death Dis 2021 Apr 9;12(4):384. Epub 2021 Apr 9.

Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital of China Medical University, Shenyang, China.

WW domain binding protein-2 (WBP2) can function as a Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) co-activator and has a crucial role in promoting breast cancer progression. However, the expression and potential molecular mechanisms of WBP2 in the context of lung cancer are not fully understood. We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the advanced pTNM stage, lymph node metastasis, and poor prognosis of patients. In addition, gain- and loss-of-function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 (WW and C2 domain-containing-3) with LATS1 (Large tumor suppressor-1) through its PPxY motifs, thus inhibiting the formation of the WWC3-LATS1 complex, reducing the phosphorylation level of LATS1, suppressing the activity of the Hippo pathway, and ultimately promoting YAP nuclear translocation. Therefore, from the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
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http://dx.doi.org/10.1038/s41419-021-03600-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035140PMC
April 2021

Expression of IFN-induced 2'-5'-oligoadenylate synthetases correlates with immune infiltration, revealing potential targets and new biomarkers for basal-like breast cancer prognosis.

Int Immunopharmacol 2020 Nov 1;88:106916. Epub 2020 Sep 1.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China; Department of Pathology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China. Electronic address:

Triple-negative breast cancer has been classified as basal-like immune activated (BLIA), basal-like immune-suppressed (BLIS), and two other subtypes, suggesting potential immune therapeutic targets for basal-like breast cancer (BLBC). 2'-5'-Oligoadenylate synthetases (OASs), identified from differentially expressed genes (DEGs) between BLIA and BLIS breast cancers (GSE76124), are involved in antiviral activity induced by interferons. However, the association between the four OASs and prognosis or tumor-infiltrating immune cells (TIICs) remains unclear. Expression, survival data, and immune correlations for OASs in BLBC were assessed using bioinformatics tools. We found that OASs were highly expressed in BLIA breast cancer. Survival analysis suggested that high transcriptional levels of OASs were associated with better overall survival, relapse-free survival, and distant metastasis-free survival in patients with BLBC. Moreover, the prognostic value of OASs with respect to different clinicopathological factors, and especially according to lymph node metastasis, in patients with BLBC was further assessed. Our findings elucidated the expression, prognostic role, and effect of OASs in TIICs on BLBC, which might promote the development of OAS-targeted immunotherapy for BLBC.
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http://dx.doi.org/10.1016/j.intimp.2020.106916DOI Listing
November 2020

FAM110B Inhibits Non-Small Cell Lung Cancer Cell Proliferation and Invasion Through Inactivating Wnt/β-Catenin Signaling.

Onco Targets Ther 2020 19;13:4373-4384. Epub 2020 May 19.

Department of Pathology, The College of Basic Medical Sciences and The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.

Purpose: FAM110B is a member of the FAM110 family (family with sequence similarity 110), which is a component of the centrosome associated proteins. Previous studies have shown that FAM110B may be involved in the process of cell cycle and may play a role in carcinogenesis and tumor progression. Using an online database, we found that FAM110B may predict favorable prognosis in non-small cell lung cancer (NSCLC). Therefore, the role of FAM110B playing in NSCLC needs to be further investigated.

Patients And Methods: Online databases and immunohistochemistry were used to predict the expression and prognostic value of FAM110B in NSCLC samples. Immunofluorescence staining was used to investigate the subcellular distribution of FAM110B. Western blot, MTT, colony formation, and matrigel invasion assay were used to detect the expression and the effect of FAM110B on mediating proliferation and invasion in NSCLC cell lines.

Results: In this study, immunohistochemistry results showed that FAM110B expression significantly correlated with early TNM staging (=0.020) and negative regional lymph node metastasis (=0.006). Kaplan-Meier survival analysis found that the median survival time of patients with positive FAM110B expression (56.181±2.348 months) was significantly longer than those with negative FAM110B expression (47.701±2.997 months, =0.024). Moreover, overexpression of FAM110B inhibited the proliferation and invasion of A549, H1299, and LK2 cell lines. Conversely, FAM110B RNAi exerted opposite effects in the above cell lines. Furthermore, FAM110B overexpression downregulated the active β-catenin, phosphorylation of GSK-3β (p-GSK-3β), cyclin B1, cyclin D1, MMP2, and MMP7, and upregulated the phosphorylation of β-catenin (p-β-catenin) in A549 and H1299 cells. Besides, the FAM110B-induced depressions of p-GSK-3β and active β-catenin were reversed after being treated with Wnt/β-catenin inhibitor, XAV-939.

Conclusion: In summary, our results demonstrated that the overexpression of FAM110B restricts the proliferation and invasion of NSCLC cells by inhibiting Wnt/β-catenin signaling. Our study reveals the antitumor function of FAM110B in NSCLC and indicates that FAM110B is a potential therapeutic target.
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http://dx.doi.org/10.2147/OTT.S247491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245470PMC
May 2020

Correction to: ZNF326 promotes malignant phenotype of glioma by up-regulating HDAC7 expression and activating Wnt pathway.

J Exp Clin Cancer Res 2020 Jan 16;39(1):14. Epub 2020 Jan 16.

Department of Pathology, College of Basic Medical Sciences, and First Affiliated Hospital of China Medical University, Shenyang, China.

In the original publication of this manuscript [1], the author mislabeled the CTL group and ZNF326 group in Fig. 2-I,J (MTT result). The revised Fig. 2 is shown below.
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http://dx.doi.org/10.1186/s13046-020-1526-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964022PMC
January 2020

FAM163A, a positive regulator of ERK signaling pathway, interacts with 14-3-3β and promotes cell proliferation in squamous cell lung carcinoma.

Onco Targets Ther 2019 13;12:6393-6406. Epub 2019 Aug 13.

Department of Pathology, The First Affiliated Hospital and the College of Basic Medical Sciences of China Medical University, Shenyang, People's Republic of China.

Purpose: FAM163A, also called neuroblastoma-derived secretory protein (NDSP) or C1ORF76, was newly found on chromosome 1q25.2. Previous studies of FAM163A focused on its expression and function in neuroblastoma. However, using an online database, we found that FAM163A may predict poor prognosis in lung squamous cell carcinomas (LUSC). Therefore, the role of FAM163A plays in LUSC needs to be further clarified.

Patients And Methods: Western blots, immunofluorescence and immunohistochemistry were used to detect the effect of FAM163A on mediating cell proliferation in vitro and in vivo. Co-immunoprecipitation and immunofluorescence were utilized to evaluate the interaction and co-localization of FAM163A with 14-3-3β and ERK.

Results: In this study, our data revealed that FAM163A overexpression increased the levels of ERK and p90RSK phosphorylation and promoted the expression of cyclin D1. Incorporation with U0126 reversed the effects of FAM163A overexpression. FAM163A directly interacted with both 14-3-3β and ERK and regulated the phosphorylation of ERK by upregulating the protein level of 14-3-3β. Immunohistochemistry results also showed that FAM163A expression significantly correlated with larger tumor size (0.023), TNM staging (0.015) and regional lymph node metastasis (0.016). Kaplan-Meier survival analysis implied the mean survival time of patients with positive FAM163A expression (49.72±3.97 months) was much shorter than the patients with negative FAM163A expression (63.36±3.14 months, 0.011).

Conclusion: In summary, the present study identified a novel mechanism that FAM163A, through binding and upregulating 14-3-3β, facilitated ERK phosphorylation that led to an increase of cellular proliferation of LUSC cells. FAM163A may be a useful marker to predict poor prognosis of patients with LUSC.
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http://dx.doi.org/10.2147/OTT.S214731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698174PMC
August 2019

Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance Induced by Membranous/Cytoplasmic/Nuclear Translocation of Epidermal Growth Factor Receptor.

J Thorac Oncol 2019 10 19;14(10):1766-1783. Epub 2019 Jun 19.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China. Electronic address:

Introduction: The molecular mechanism underlying the induction of resistance to tyrosine kinase inhibitors (TKIs) via the membranous/cytoplasmic/nuclear translocation of EGFR has not yet been reported.

Methods: We performed immunohistochemistry to detect the distribution of EGFR in lung adenocarcinoma specimens after TKI treatment and analyzed the relationship between different EGFR locations and patient survival duration. Mass spectrometry analysis and immunoprecipitation were performed to show the interaction of cytosolic EGFR with YY1 associated protein 1 (YAP) and salt inducible kinase 2 (SIK2). Dual-luciferase assays, immunoblotting, real-time polymerase chain reaction, and functional experiments were used to elucidate the role of EGFR cytoplasmic/nuclear translocation in Hippo pathway dysregulation.

Results: Patients with advanced lung adenocarcinoma with membranous mutant EGFR (19del or 21 L858R) showed significantly longer progression-free survival than those with cytoplasmic mutant EGFR after gefitinib treatment. The concentration that inhibits 50% in PC-9 with cytoplasmic EGFR was higher than that in hunman non-small cell lung cancer 827 with membranous EGFR. During first-generation TKI resistance induction, membrane EGFR translocated to the cytoplasm/nucleus, accompanied by the Hippo pathway inhibition. Cytoplasmic EGFR and SIK2 interaction inhibited large tumor suppressor kinase 1 (LATS1) and macrophage stimulating 1 (MST1) interaction, promoting YAP nuclear translocation. However, cells with osimertinib-induced resistance also showed EGFR translocation and lower phospho-EGF receptor but did not show Hippo pathway inhibition. Moreover, osimertinib and erlotinib could restore sensitivity to each other in resistant cells.

Conclusions: Plasma/nuclear translocation of EGFR and inhibition of the Hippo pathway are some of the important mechanisms underlying the resistance induced by first-generation TKIs. Membrane/plasma translocation of EGFR induced by osimertinib may be another resistance phenomenon besides MNNG HOS transforming gene (c-MET) amplification, C797S mutation, and ERK pathway inhibition.
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http://dx.doi.org/10.1016/j.jtho.2019.06.014DOI Listing
October 2019

Fbxo6 confers drug-sensitization to cisplatin via inhibiting the activation of Chk1 in non-small cell lung cancer.

FEBS Lett 2019 07 7;593(14):1827-1836. Epub 2019 Jun 7.

Department of Pathology, The First Affiliated Hospital and the Basic Medical Sciences of China Medical University, Shenyang, China.

Fbxo6 (also called FBG2) is a critical component of the evolutionarily conserved ubiquitin-protein ligase complex SCF (Skp1/Cdc53-Cullin1/F-box). Previous studies have demonstrated that Fbxo6 facilitates the growth and proliferation but inhibits the apoptosis and invasion of gastric cancer cells. However, the role of Fbxo6 in non-small cell lung cancer (NSCLC) is still not clear. Our results revealed that Fbxo6 expression is correlated with early TNM stage and favorable overall survival of NSCLC patients. Further in vitro experiments showed that Fbxo6 inhibits proliferation, facilitates apoptosis and promotes the sensitivity of cisplatin via decreased expression and phosphorylation of Chk1. Thus, Fbxo6 may be a useful prognosis marker and therapeutic target to overcome the chemoresistance of cisplatin-based chemotherapy agents in NSCLC patients.
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http://dx.doi.org/10.1002/1873-3468.13461DOI Listing
July 2019

ZNF326 promotes malignant phenotype of glioma by up-regulating HDAC7 expression and activating Wnt pathway.

J Exp Clin Cancer Res 2019 Jan 28;38(1):40. Epub 2019 Jan 28.

Department of Pathology, College of Basic Medical Sciences, and First Affiliated Hospital of China Medical University, Shenyang, China.

Background: Zinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, however, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood.

Methods: Immunohistochemistry was applied to detect the expression of ZNF326 in glioma tissues, and statistical analysis was used to analyse the relationship between ZNF326 expression and clinicopathological factors. The effect of ZNF326 on glioma cells proliferation and invasion was conducted by functional experiments both in vivo and in vitro. Chromatin immunoprecipitation and dual-luciferase assays were performed to demonstrate that histone deacetylase enzyme-7 (HDAC7) is the target gene of ZNF326. Immunoblotting, real-time PCR, GST-pulldown and co-immunoprecipitation assays were used to clarify the underlying role of ZNF326 on Wnt pathway activation.

Results: High nuclear expression of ZNF326 was observed in glioma cell lines and tissues, and closely related with advanced tumour grade in the patients. Moreover, ectopic ZNF326 expression promoted the proliferation and invasiveness of glioma cells. Mechanistically, ZNF326 could activate HDAC7 transcription by binding to a specific promoter region via its transcriptional activation domain and zinc-finger structures. The interaction of the up-regulated HDAC7 with β-catenin led to a decrease in β-catenin acetylation level at Lys-49, followed by a decrease in β-catenin phosphorylation level at Ser-45. These changes in β-catenin posttranscriptional modification levels promoted its redistribution and import into the nucleus. Additionally, ZNF326 directly associated with β-catenin in the nucleus, and enhanced the binding of β-catenin to TCF-4, serving as a co-activator in stimulating Wnt pathway.

Conclusions: Our findings elucidated ZNF326 promotes the malignant phenotype of human glioma via ZNF326-HDAC7-β-catenin signalling. This study reveals the vital role and mechanism of ZNF326 in the malignant progression of glioma, and provides the reference for finding biomarkers and therapeutic targets for glioma.
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http://dx.doi.org/10.1186/s13046-019-1031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350303PMC
January 2019

TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients.

Mol Carcinog 2019 05 22;58(5):767-776. Epub 2019 Jan 22.

Department of Pathology, College of Basic Medical Science and the First Affiliated Hospital of China Medical University, Shenyang, China.

TIMM50 (Translocase of the inner mitochondrial membrane 50), also called TIM50, plays an essential role in mitochondrial membrane transportation. The existing literature suggests that TIMM50 may perform as an oncogenetic protein in breast cancer. However, the molecular mechanism, especially in human non-small cell lung cancer (NSCLC), is uncertain to date. In the present study, using immunohistochemistry, we found that TIMM50 expression significantly correlated with larger tumor size (P = 0.049), advanced TNM stage (P = 0.001), positive regional lymph node metastasis (P = 0.007), and poor overall survival (P = 0.001). Proliferation and invasion assay showed that TIMM50 dramatically promoted the ability of proliferation and invasion of NSCLC cells. Subsequent Western blotting results revealed that TIMM50 enhanced the expression of Cyclin D1 and Snail, and inhibited the expression of E-cadherin. Moreover, TIMM50 facilitated the expression of phosphorylated ERK and P90RSK. Incorporation of ERK inhibitor counteracted the upregulating expression of CyclinD1, and Snail, and downregulating expression of E-cadherin expression induced by TIMM50 overexpression. In conclusion, our data indicated that TIMM50 facilitated tumor proliferation and invasion of NSCLC through enhancing phosphorylation of its downstream ERK/P90RSK signaling pathway. We speculated that TIMM50 might be a useful prognosis marker of NSCLC patients.
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http://dx.doi.org/10.1002/mc.22969DOI Listing
May 2019

TMEM206 promotes the malignancy of colorectal cancer cells by interacting with AKT and extracellular signal-regulated kinase signaling pathways.

J Cell Physiol 2019 07 11;234(7):10888-10898. Epub 2018 Nov 11.

Department of Gastrointestinal Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.

Background: The roles of TMEM206, a new transmembrane protein, in cancer, including colorectal cancer (CRC), are unknown. Related family members, including TMEM16A, TMEM132A, and TMEM176B, have been shown to be involved in various biological behaviors. In addition, TMEM88 has been reported to promote non-small-cell lung cancer. In this study, we examined the roles of TMEM206 in CRC.

Method: Real-time reverse transcription polymerase chain reaction was used to measure TMEM206 messenger RNA (mRNA) levels in clinical specimens and transfected cell lines. Immunohistochemistry was used to determine the relationship between TMEM206 expression levels and clinical data. Plasmids and small interfering RNA were used to upregulate and silence TMEM206, respectively. Protein expression levels and signaling pathway modulation were validated through western blot analysis. Colony formation, MTT, cell migration and invasion assays, and flow cytometry analyses were used to test the potential roles of TMEM206 in CRC. Co-immunoprecipitation was used to evaluate the interaction between TMEM206 and AKT.

Results: Investigation of the clinical significance of TMEM206 expression in CRC tissues revealed that TMEM206 mRNA and protein levels were higher in CRC tissues than in paired normal adjacent tissues (p < 0.05). TMEM206 overexpression was positively associated with T stage of cancer and UICC stage ( p < 0.05) and negatively related to differentiation of CRC ( p = 0.015). Upregulation or silencing of TMEM206 promoted or inhibited the proliferation of CRC cells and positively or negatively regulated the levels of phospho-AKT and downstream signaling pathway components (phospho-glycogen synthase kinase 3β and cyclin D1), respectively. Moreover, silencing of TMEM206 in cell lines arrested CRC cells in the G1 stage of the cell-cycle. In addition, upregulating or silencing TMEM206 increased or decreased cell invasion and migration in vitro and positively or negatively altered levels of the phospho-extracellular signal-regulated kinase (ERK) and phospho-focal adhesion kinase 397, respectively. Co-immunoprecipitation demonstrated that AKT and TMEM206 proteins interacted. Furthermore, TMEM206 promoted the development and progression of CRC by enhancing the interactions between the AKT and ERK signaling pathways.

Conclusion: TMEM206 controlled the progression of CRC by accelerating CRC cell proliferation and promoting CRC cell migration and invasion. The target of TMEM206 may be AKT, which is known to be involved in modulating the biological behaviors of various cancers.
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http://dx.doi.org/10.1002/jcp.27751DOI Listing
July 2019

ZNF326 promotes proliferation of non-small cell lung cancer cells by regulating ERCC1 expression.

Lab Invest 2019 02 6;99(2):169-179. Epub 2018 Nov 6.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, PR China.

The roles and downstream target genes of the transcription factor ZNF326 in malignant tumors are unclear. Out of 146 lung cancer tissue samples, we found that high expression of ZNF326 in 82 samples was closely related to low differentiation and a high pTNM stage of non-small cell lung cancer (NSCLC) cells. In vitro and in vivo analyses showed that ZNF326 significantly promoted cell cycle progression, colony formation, and proliferation as well as the growth of NSCLC transplanted tumors. Chromatin immunoprecipitation sequencing, dual-luciferase assay, and electrophoretic mobility shift assay confirmed that the C2H2 structure of ZNF326 binds to the -833 to -875 bp region of the ERCC1 promoter to initiate transcriptional activity. This binding promoted CyclinB1 synthesis and cell cycle progression. These results show that the ZNF326 transcription factor is highly expressed in lung cancer and promotes the proliferation of NSCLC cells by regulating the expression of ERCC1.
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http://dx.doi.org/10.1038/s41374-018-0148-yDOI Listing
February 2019

ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling.

J Cell Physiol 2019 06 12;234(6):8899-8907. Epub 2018 Oct 12.

Department of General Surgery, Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, China.

ZC3H13 is a canonical CCCH zinc finger protein, which harbors a somatic frame-shift mutation in colorectal cancer (CRC). However, its expression and biological function were still uncertain. In the current study, we found that ZC3H13 was served as a tumor suppressor in CRC cells, which decreased the expression of Snail, Cyclin D1, and Cyclin E1, and increased the expression of Occludin and Zo-1 through inactivating Ras-ERK signaling pathway. Furthermore, reduction of ZC3H13 associated with advanced TNM stage (p = 0.02), positive regional lymph node metastasis ( p = 0.01). Taken together, the current study indicated that ZC3H13 may be an upstream regulator of Ras-ERK signaling pathway and suppressed invasion and proliferation of CRC.
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http://dx.doi.org/10.1002/jcp.27551DOI Listing
June 2019

Alveolar architectures preserved in cancer tissues may be potential pitfalls for diagnosis and histological subtyping of lung cancer: Three case reports.

Medicine (Baltimore) 2018 Sep;97(39):e12613

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.

Rationale: Lung cancer is a leading cause of cancer-related deaths globally. Appropriate histopathological diagnosis and subtyping form the basis and are critical for clinical therapies.

Patient Concerns: Here, we report about 3 patients who had a nodule in the lung. Cancer cells grow in the alveolar cavity in many lung carcinomas. In all our 3 cases preserved alveolar architectures were found in tumor tissues which may lead to diagnostic pitfalls.

Diagnoses: Three patients had tumors that were diagnosed as nonsmall cell lung cancers, including large-cell carcinoma, peripheral squamous cell carcinoma, and large-cell neuroendocrine carcinoma, all of which contained structures of preserved alveolar cells that could be mistaken as malignant glandular components. The preserved alveolar cells formed acinar or duct-like structures enwrapped in the lung cancer tissues or surrounded the nests of cancer cells. Proliferative alveolar cells adjacent to cancer tissues were observed, and papillary structures and marked atypia, both of which may be mistaken as part of adenocarcinoma or carcinoma with glandular differentiation, were also observed.

Interventions: All patients underwent surgery and postoperative chemotherapy.

Outcomes: The patients had no recurrence at 5-, 8-, or 10-month follow-up after the last surgery.

Lessons: Preserved alveolar cells with different architectures may be observed in various lung cancer tissues and may be mistaken as adenocarcinoma or carcinoma with glandular differentiation. Distinct morphological and immunohistochemical features may help distinguish preserved alveolar cells from tumor components.
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http://dx.doi.org/10.1097/MD.0000000000012613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181608PMC
September 2018

CCDC85B promotes non-small cell lung cancer cell proliferation and invasion.

Mol Carcinog 2019 01 9;58(1):126-134. Epub 2018 Oct 9.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3β phosphorylation and upregulated the levels of active β-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B-induced upregulation of phosphorylated GSK3β and active β-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3β/β-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment.
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http://dx.doi.org/10.1002/mc.22914DOI Listing
January 2019

Long period of relative quiescence in distal-type epithelioid sarcoma of the forearm with recurrence after surgery: A case report.

Medicine (Baltimore) 2018 Sep;97(36):e12276

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.

Background: Epithelioid sarcoma (ES) is a rare malignant mesenchymal tumor that only accounts for 0.6% to 1.0% of all cases of sarcomas. ES with a relative quiescent state of more than 10 years is extremely rare.Here, we present a rare case of ES in the forearm of a 17-year-old girl. The patient had a congenital mass in her forearm that measured approximately 1cm; it grew rapidly starting 5 years ago. The mass was not treated until last year when she underwent the first surgery. The mass was located in the middle and lower part of the left forearm and involved the dorsal muscle group, intermuscular space, and subcutaneous tissues without clear boundaries.The patient underwent surgery, and the tumor recurred twice within 1 year postoperatively.

Methods: The tumor samples were examined via hematoxylin-eosin (HE) and immunohistochemistry staining.

Results: Histopathologically, the tumor comprised large polygonal epithelioid cells with abundant eosinophilic cytoplasm arranged in cell nests. Central necrosis and focal myxoid change could be seen in the tumor tissues. Immunostaining showed that the tumor cells were positive for CD34, CK, EMA, and vimentin but negative for CD31, S-100, and INI-1.

Conclusion: Based on these findings, the tumor was diagnosed as ES of distal form. Distal-type ES could have a long period of relative quiescence, after which it could grow rapidly and relapse multiple times over a short duration.
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http://dx.doi.org/10.1097/MD.0000000000012276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133439PMC
September 2018

ZNF326 promotes a malignant phenotype of breast cancer by interacting with DBC1.

Mol Carcinog 2018 12 20;57(12):1803-1815. Epub 2018 Sep 20.

Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China.

The biological role and underlying mechanism of action of zinc-finger protein 326 (ZNF326) in malignant tumors, including breast cancer, are still not clear. In this study, we detected high expression of ZNF326 in breast cancer specimens (60/111, 54.1%) and breast cancer cell lines (7/7); the expression level of ZNF326 was inversely associated with advanced pTNM stage (P = 0.002), positive lymph node metastasis (P = 0.004), poor prognosis in patients with breast cancer (P = 0.0097), and ER/PR/Her2 status (P = 0.013). Meanwhile, the ectopic expression of ZNF326 significantly upregulated MMP7, EMT-related proteins (Snail and Slug), and cell cycle-related proteins (cyclinA2 and cyclinB1); downregulated E-cadherin expression; and promoted the proliferation and invasiveness of breast cancer cells both in vivo and in vitro. Mechanistically, co-immunoprecipitation and immunofluorescence assays both demonstrated that ZNF326 interacted with deleted in breast cancer-1 (DBC1) in breast cancer cells. Additionally, DBC1 knockdown eliminated the up-regulation of MMP7, EMT-related proteins, and cell cycle-related proteins as well as the enhanced proliferation and invasiveness induced by ZNF326. Therefore, we concluded that ZNF326 is highly expressed in breast cancer, is associated with poor prognosis, and plays a vital role in promoting the malignant phenotype of breast cancer cells by interacting with DBC1.
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http://dx.doi.org/10.1002/mc.22898DOI Listing
December 2018

TMEM17 promotes malignant progression of breast cancer via AKT/GSK3β signaling.

Cancer Manag Res 2018 2;10:2419-2428. Epub 2018 Aug 2.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China,

Purpose: Current knowledge of TMEM17, a recently identified protein of the transmembrane (TMEM) family, is limited, especially with respect to its expression and biological functions in malignant tumors. This study analyzed TMEM17 expression in invasive breast cancer tissue and breast cell lines and its relevance to clinicopathological factors, and investigated the mechanisms underlying the biological effects of TMEM17 on breast cancer cells.

Patients And Methods: TMEM17 protein expression was determined in 20 freshly harvested specimens (tumor and paired normal tissues) by Western blotting. Immunohistochemical analysis was performed to determine the expression and subcellular localization of TMEM17 in samples from 167 patients (mean age, 49 years) diagnosed with invasive ductal carcinoma (38 with triple-negative breast cancer; 129 with non-triple-negative breast cancer) who underwent complete resection in the First Affiliated Hospital of China Medical University between 2011 and 2013. Furthermore, TMEM17 was knocked down by small interfering RNAs in breast cancer cell lines.

Results: TMEM17 was found to be significantly upregulated in breast cancer tissues compared to the corresponding normal breast tissues by Western blotting (=0.015). Immunohistochemical analysis revealed that TMEM was significantly upregulated in invasive breast cancer cells compared to adjacent normal breast duct glandular epithelial cells (10.78% vs 76.05%, <0.001), and its expression was closely related to the patient's T-stage (=0.022), advanced TNM stages (=0.007), and lymph node metastasis (=0.012). After TMEM17 knockdown or overexpression in breast cancer cell lines, TMEM17 upregulated p-AKT, p-GSK3β, active β-catenin, and Snail, and downstream target proteins c-myc and cyclin D1, and downregulated E-cadherin, resulting in increased cancer cell proliferation, invasion, and migration. These effects were reversed by the AKT inhibitor LY294002.

Conclusion: Our results indicate that TMEM17 is upregulated in breast cancer tissues and can promote malignant progression of breast cancer cells by activating the AKT/GSK3β signaling pathway.
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http://dx.doi.org/10.2147/CMAR.S168723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080873PMC
August 2018

miR‑1 inhibits the progression of colon cancer by regulating the expression of vascular endothelial growth factor.

Oncol Rep 2018 Aug 24;40(2):589-598. Epub 2018 May 24.

Department of General Surgery, Gastrointestinal Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

MicroRNA (miR)‑1 is associated with various human malignancies through repressing tumor growth, migration and angiogenesis. Recently, high‑throughput transcriptional profiling confirmed that miR‑1 is markedly downregulated in metastatic colorectal cancer; however, its biological functions and the specific underlying mechanisms in colorectal cancer (CRC) require further investigation. In this study, the expression of miR‑1 in 111 CRC and paired normal tissue samples was measured using quantitative polymerase chain reaction analysis, and the association between miR‑1 expression and clinical characteristics was evaluated. miR‑1 was found to be significantly downregulated in CRC tissues compared with paired normal tissues, and in CRC cell lines compared with non‑cancer cells (P<0.001), and was negatively associated with tumor size (P=0.001), differentiation (P=0.011), lymph node metastasis (P=0.001) and TNM stage (P=0.001). Further experiments revealed that miR‑1 inhibited the migration and invasion of HCT116 and ClonA1 cells, and inhibited cell proliferation by affecting the cell cycle. Vascular endothelial growth factor (VEGF) was found to be a potential target of miR‑1 by biological prediction, and further investigation confirmed that miR‑1 significantly inhibited the expression and paracrine function of VEGF. In CRC tissues, the expression of VEGF was negatively correlated with miR‑1. The low expression of miR‑1 in CRC may be one of the reasons for the abnormally high expression of VEGF; the upregulation of miR‑1 expression may inhibit cancer progression by downregulating VEGF. These findings indicate that treatment with miR‑1 may be a novel method of tumor suppression, and provide a theoretical and experimental basis for the further targeted treatment of CRC through the regulation of miR‑1 and VEGF expression.
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http://dx.doi.org/10.3892/or.2018.6463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072287PMC
August 2018

WWC3 inhibits epithelial-mesenchymal transition of lung cancer by activating Hippo-YAP signaling.

Onco Targets Ther 2018 8;11:2581-2591. Epub 2018 May 8.

Department of Pathology, College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.

Background: Though we recently reported that the WWC3 inhibits the invasiveness and metastasis of lung cancer by activating the Hippo pathway, the impact and underlying mechanisms of this process still remain unclear.

Methods: To identify the role of WWC3 in epithelial-mesenchymal transition of lung cancer, we performed immunohistochemistry to detect the expression levels of WWC3 and EMT-related biomarker, and analyzed their correlations in a cohort of 127 patients with NSCLC. Wound healing assay and cell invasion assay were applied to explore cell invasive ability change after WWC3 knockdown. qRT-PCR and immunoblotting were performed to assess mRNA and protein levels of EMT-related biomarkers and the main molecules changes of Hippo signaling caused by WWC3. Immunoprecipition was to examine WWC3 and LATS1 interaction.

Results: WWC3 knockdown drives a pronounced shift from the epithelial to the mesenchymal phenotype in lung cancer cells. In addition, WWC3 ectopic expression in lung cancer cells attenuates mesenchymal markers and increases the epithelial markers expressions; however, WWC3-ΔWW plasmid abrogated these effects. WWC3 silencing by shRNA exerts the opposite effect. Furthermore, WWC3 levels were inversely correlated with the levels of EMT inducers (Snail and Slug) in lung cancer cells and specimens. Immunoblotting revealed that WWC3 wild-type upregulates large tumor suppressor (LATS1) and yes-associated protein (YAP) phosphorylation through its WW domain, hence activating Hippo pathway. Knockdown of YAP and LATS1, as well as the as the Verteporfin (VP) usage, could reverse this effect caused by WWC3 silencing.

Conclusion: These findings suggest that WWC3 works as a tumor suppressor to inhibit EMT process and confer its candidacy as a potential therapeutic target in lung cancer.
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http://dx.doi.org/10.2147/OTT.S162387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951220PMC
May 2018

Zinc finger protein 668 suppresses non-small cell lung cancer invasion and migration by downregulating Snail and upregulating E-cadherin and zonula occludens-1.

Oncol Lett 2018 Mar 16;15(3):3806-3813. Epub 2018 Jan 16.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.

Zinc finger protein 668 (ZNF668) is a recently discovered protein and its expression levels, as well as its involvement in the invasion and metastasis of non-small cell lung cancer (NSCLC), are largely unknown. In the present study, immunohistochemical analysis demonstrated that ZNF668 protein expression was decreased in lung tumors (51/167, 30.5%) compared with adjacent normal lung tissues (43/62, 69.4%; P<0.001). Subsequent statistical analysis revealed that ZNF668 expression was negatively associated with increased tumor-node-metastasis stage (P=0.019) and lymph node metastasis (P=0.002). Following ZNF668 downregulation by transfection of a -expressing plasmid or small interfering RNA, it was demonstrated that ZNF668 inhibited the invasion and migration of NSCLC cells. Furthermore, restoration of ZNF668 expression downregulated the expression of Snail and increased the protein levels of epithelial (E-)cadherin and zonula occludens-1 (ZO-1). The results of the present study suggest that ZNF668 is downregulated in human NSCLC. Furthermore, restoration of ZNF668 expression was demonstrated to decrease the expression of Snail and increase the expression of E-cadherin and ZO-1, suppressing the invasion and migration of NSCLC cells.
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http://dx.doi.org/10.3892/ol.2018.7802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844101PMC
March 2018

E3 ubiquitin ligase tripartite motif-containing 71 promotes the proliferation of non-small cell lung cancer through the inhibitor of kappaB-α/nuclear factor kappaB pathway.

Oncotarget 2018 Feb 7;9(13):10880-10890. Epub 2017 Jul 7.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, China.

Tripartite motif-containing (TRIM) 71 belongs to the TRIM protein family. Many studies have shown that TRIM71 plays conserved roles in stem cell proliferation, differentiation, and embryonic development; however, the relationship between TRIM71 and tumorigenesis is not clear. In this study, we demonstrate that TRIM71 expression in non-small cell lung cancer (NSCLC) is associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis. We found that TRIM71 was highly expressed in NSCLC cell lines compared with that in human normal bronchial epithelial cells. Moreover, by altering the expression of TRIM71 in selected cell lines, we found that TRIM71 promoted the proliferation of NSCLC cells through activation of the inhibitor of kappaB/nuclear factor kappaB pathway. These results suggested that TRIM71 plays a role in promoting the development of NSCLC.
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http://dx.doi.org/10.18632/oncotarget.19075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834285PMC
February 2018

ARHGEF39 promotes tumor progression via activation of Rac1/P38 MAPK/ATF2 signaling and predicts poor prognosis in non-small cell lung cancer patients.

Lab Invest 2018 05 30;98(5):670-681. Epub 2018 Jan 30.

Department of Pathology, The College of Basic Medicine Science and The First Affiliated Hospital of China Medical University, Shenyang, China.

Rho guanine nucleotide exchange factor 39 (ARHGEF39), also called C9orf100, is a new member of the Dbl-family of guanine nucleotide exchange factors. Although ARHGEF39 has been proven to regulate tumor progression in hepatocellular carcinoma, the downstream signaling pathway of ARHGEF39 and its clinical associations in non-small cell lung cancer (NSCLC) are currently unknown. In the present study, using MTT, colony formation, flow cytometry, mice xenografts, wound healing, and transwell assays, we showed that ARHGEF39 promoted tumor proliferation, migration, and invasion. Furthermore, ARHGEF39 promoted the expression of Cyclin A2, Cyclin D1, and MMP2 by activating Rac1, leading to increased phosphorylation of P38 and ATF2. Treatment with a P38 inhibitor counteracted the effect of ARHGEF39 overexpression on the increase in Cyclin A2, Cyclin D1, and MMP2 expression. Moreover, the elevated levels of p-P38 and p-ATF2 caused by ARHGEF39 overexpression could be inhibited by expression of a dominant negative Rac1 mutant (T17N). In addition, the inhibition of the expression of p-P38 and p-ATF2 by ARHGEF39 RNAi could be restored by the expression of a constitutively active Rac1 mutant (Q61L). A similar impact on cell growth and invasion was observed after ARHGEF39 overexpression combined with the P38 inhibitor, Rac1 T17N, or Rac1 Q61L. Using immunohistochemistry, ARHGEF39 expression was observed to correlate positively with larger tumor size in clinical samples from 109 cases of NSCLC (P = 0.008). The Kaplan-Meier test revealed that ARHGEF39 expression significantly affected the overall survival of patients with NSCLC (52.55 ± 6.40 months vs. 64.30 ± 5.40 months, P = 0.017). In conclusion, we identified that ARHGEF39 promotes tumor growth and invasion by activating the Rac1-P38-ATF2 signaling pathway, as well as increasing the expression of Cyclin A2, Cyclin D1, and MMP2 in NSCLC cells. ARHGEF39 may be a useful marker to predict poor prognosis of patients with NSCLC.
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http://dx.doi.org/10.1038/s41374-018-0022-yDOI Listing
May 2018

DDIAS promotes invasion and proliferation of non-small cell lung cancer and predicts poor survival of lung cancer patients.

Int J Clin Exp Pathol 2017 1;10(12):11506-11515. Epub 2017 Dec 1.

Department of Pathology, The First Affiliated Hospital, The College of Basic Medicine Science of China Medical University Shenyang, China.

DNA damage-induced apoptosis suppressor (DDIAS), also called hNoxin or C11 or f82, is an anti-apoptotic protein in response to stress. The clinicopathological significance of DDIAS in non-small cell lung cancer patients is largely unknown until now. The purpose of our study is to analyze the clinicopathological association of DDIAS in NSCLC patients. We found that the positive ratio of DDIAS was significantly higher than that in the corresponding non-cancerous lung tissues (<0.001). Positive DDIAS expression correlated with larger tumor size and positive regional lymph node metastasis (=0.048 and =0.018, respectively). Online Kaplan-Meier Plotter tool analysis results and survival analysis results of our cohort revealed that both DDIAS gene level (=0.0048) and protein level (<0.001) were associated with adverse outcome in NSCLC patients for overall survival, as well as in multiple subgroups divided by different clinicopathological features. Subsequent univariate and multivariate analysis suggested that only positive DDIAS was an independent prognostic factor for overall survival (=0.018). In NSCLC cell lines, overexpression of DDIAS enhanced the ability of invasion and proliferation, whereas depleting DDIAS depressed the ability of invasion and proliferation. In conclusion, our results suggest that positive DDIAS expression may be a potent prognostic factor in NSCLC patients. DDIAS promotes proliferation and invasion in NSCLC cells and correlates with progression of NSCLC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966031PMC
December 2017

The coiled-coil domain of oncogene RASSF 7 inhibits hippo signaling and promotes non-small cell lung cancer.

Oncotarget 2017 Oct 12;8(45):78734-78748. Epub 2017 Aug 12.

Department of Pathology, College of Basic Medical Science and First Affiliated Hospital, China Medical University, Shenyang, China.

Lung cancer is the leading cause of cancer-related deaths worldwide, and despite recent improvements in treatment patient prognosis remains dismal. In this study, we examined the role of N-terminal Ras-association domain family 7 (RASSF7) in human non-small cell lung cancer (NSCLC). We found that RASSF7 was overexpressed NSCLC tissues, which correlated with advanced TNM stage, positive lymph node metastasis, and poor prognosis. This RASSF7 overexpression promoted lung cancer cell proliferation, migration, and invasion. We also found that RASSF7 interacted with mammalian Ste20-like kinase 1(MST1) through its C-terminal coiled-coil domain to inhibit MST1 phosphorylation as well as the phosphorylation of large tumor suppressor kinase 1(LATS1) and yes-associated protein (YAP), while promoting the nuclear translocation of YAP. In addition, RASSF7 overexpression inhibited the Hippo signaling pathway both in and and promoted the expression of proteins associated with proliferation and invasion, such as connective tissue growth factor. These results suggest that targeting RASSF7 could be exploited for therapeutic benefit in the treatment of NSCLC.
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http://dx.doi.org/10.18632/oncotarget.20223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667994PMC
October 2017

Lasp1 promotes malignant phenotype of non-small-cell lung cancer via inducing phosphorylation of FAK-AKT pathway.

Oncotarget 2017 Sep 24;8(43):75102-75113. Epub 2017 Aug 24.

Department of Pathology, Basic Medicine Science and First Hospital of China Medical University, Shenyang, China.

Lasp1 (LIM and SH3 domain protein 1) promotes tumor proliferation and invasion in multiple cancer entities including non-small cell lung cancer (NSCLC). However, the molecular mechanism is uncertain to date. In the present study, using immunohistochemistry, we found that Lasp1 expression was significantly correlated with tumor size (=0.005), advanced TNM stage (=0.042), positive regional lymph node metastasis (=0.034) and poor overall survival (<0.001). Similar results were seen in patients with squamous cell lung carcinoma (=0.003 for larger tumor size, =0.017 for advanced TNM stage, =0.003 for positive lymph node metastasis and <0.001 for poor overall survival) but not in patients with lung adenocarcinoma (>0.05). Proliferation and invasion assay showed that Lasp1 dramatically promoted the ability of proliferation and invasion of NSCLC cells. Subsequent western blot results revealed that Lasp1 promoted the expression of Cyclin A2, CyclinB1, and Snail, and inhibited the expression of E-cadherin. Lasp1 directly interacted with FAK and facilitated the expression of phosphorylated FAK (Tyr397) and AKT (Ser473). Incorporation of both FAK inhibitor and AKT inhibitor counteracted the upregulating expression of Cyclin A2, CyclinB1, and Snail, and downregulating expression of E-cadherin expression induced by Lasp1 overexpression. Interestingly, inhibition of FAK signaling pathway attenuated the phosphorylation of AKT, but inhibition of AKT signaling pathway did not affect the phosphorylation of FAK. In conclusion, Lasp1 facilitated tumor proliferation and invasion of NSCLC through directly binding to FAK and enhancing the phosphorylation of FAK (Tyr397) and AKT (Ser473). Lasp1 may be a novel therapeutic target in the treatment of NSCLC patients.
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http://dx.doi.org/10.18632/oncotarget.20527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650404PMC
September 2017

TMEM17 depresses invasion and metastasis in lung cancer cells via ERK signaling pathway.

Oncotarget 2017 Sep 7;8(41):70685-70694. Epub 2017 Aug 7.

Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China.

Transmembrane protein 17(TMEM17) is a newly identified protein, its expression pattern and clinicopathological relevance is still unclear. In this study, western blot assay was performed in 20 paired lung cancer samples and found that TMEM17 protein levels were lower in lung cancer tissues than that in the corresponding normal lung tissues (p=0.010). Immunohistochemistry staining in 143 cases lung cancer specimens also showed that TMEM17 expression in lung cancer tissues were significantly lower than adjacent normal lung tissues (35.7% 63.2%, p<0.001). And negative TMEM17 expression was significantly associated with poor histological differentiation (p=0.027), advanced TNM stages (p=0.006), positive lymph node metastasis (p=0.002) and poor prognosis (p=0.002). After overexpressing TMEM17, levels of p-ERK and its downstream molecules, p-P90RSK and Snail, were down-regulated, while levels of Occludin and Zo-1 were up-regulated, which result in the inhibition of invasion and migration ability of lung cancer cells. The effects were reversed by the incorporation of specific ERK inhibitor PD98059. In conclusion, loss of TMEM17 correlates with the development of non-small cell lung cancer (NSCLC) and predicts adverse clinical outcome of NSCLC patients. The effect of TMEM17 on inhibiting invasion and migration may attribute to restoring Occludin and Zo-1 expression through inactivating ERK-P90RSK-Snail pathway.
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http://dx.doi.org/10.18632/oncotarget.19977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642586PMC
September 2017

Alex3 suppresses non-small cell lung cancer invasion via AKT/Slug/E-cadherin pathway.

Tumour Biol 2017 Jul;39(7):1010428317701441

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Alex3, is a newly identified mitochondrial protein, regulates mitochondrial dynamics and is involved in neural development. However, its expression pattern and clinicopathological relevance in human tumors are still unclear. In this study, Immunohistochemistry assay was performed in 109 cases of lung cancer samples and found that Alex 3 expression in lung cancer tissues was significantly lower than adjacent normal lung tissues (28.4% vs 52.6%, p < 0.001). Sequent statistical analysis indicated that negative Alex3 expression was significantly associated with advanced tumor-node-metastasis stages (p = 0.001), positive lymph node metastasis (p = 0.005), and poor prognosis (p = 0.008). After overexpression of Alex3, levels of p-AKT and Slug were downregulated, while level of E-cadherin was upregulated, which results in the inhibition of invasion and migration ability of lung cancer cells. In conclusion, reduction of Alex3 correlates with the development of non-small cell lung cancer and predicts adverse clinical outcome of non-small cell lung cancer patients. The effect of Alex3 on inhibiting invasion and migration may attribute to upregulation of E-cadherin expression through AKT-Slug pathway inactivation.
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http://dx.doi.org/10.1177/1010428317701441DOI Listing
July 2017

Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non-small cell lung cancer patients.

Mol Carcinog 2017 Dec 3;56(12):2558-2565. Epub 2017 Aug 3.

Department of Pathology, Basic Medicine Science and First Hospital of China Medical University, Shenyang, China.

Lasp2, as well as Lasp1, is a member of the LIM-protein subfamily of the nebulin group characterized by the combined presence of LIM and SH3 domains. Lasp1 and Lasp2 are highly conserved in their LIM, nebulin-like, and SH3 domains but differ significantly at their linker regions. Lasp1 had been described as an oncogenic protein that was highly expressed in diverse cancer types and facilitated tumor proliferation, invasion, and metastasis process. However, unlike Lasp1, little is known about the functions of Lasp2. In the present study, using immunohistochemistry, we found that Lasp2 expression was significantly correlated with histological type (P = 0.012), advanced TNM stage (P = 0.024), positive regional lymph node metastasis (P = 0.035), and poor overall survival (P = 0.001). Would healing assay and transwell assay results indicated that Lasp2 promoted tumor migration and invasion in NSCLC cells. Furthermore, Lasp2 facilitated Snail expression and inhibited Zo-1. The levels of phosphorylated FAK (Tyr397 and Tyr925) were obviously increased after overexpressing Lasp2 and were downregulated by transfecting Lasp2-siRNA. FAK inhibitor counteracted upregulating Snail expression and downregulating of Zo-1 expression induced by Lasp2 overexpression. Taken together, Lasp2 may facilitate tumor migration and invasion of NSCLCs through FAK-Snail/Zo-1 signaling pathway. Lasp2 may be a potential prognostic predictor of NSCLC patients.
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http://dx.doi.org/10.1002/mc.22700DOI Listing
December 2017

Noxin promotes proliferation of breast cancer cells via P38-ATF2 signaling pathway.

Tumour Biol 2017 Jun;39(6):1010428317705515

1 Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Noxin (also called chromosome 11 open reading frame 82 or DNA damage-induced apoptosis suppressor) is associated with anti-apoptosis and cell proliferation in response to stress signals. However, to our knowledge, the role of Noxin in regulating cell proliferation is still controversial and there are no reports of the function and clinicopathological association in breast cancer. In this study, immunohistochemistry results showed that Noxin expression was significantly correlated with advanced tumor-node-metastasis stage ( p = 0.027), positive regional lymph node metastasis ( p = 0.002), and poor overall survival ( p = 0.002). Proliferation assay results showed that Noxin obviously promoted the ability of proliferation of normal breast cells. Subsequent western blot results revealed that Cyclin D1 and Cyclin E1 were upregulated by overexpressing Noxin, whereas Cyclin D1 and Cyclin E1 were downregulated after depleting Noxin. The levels of phosphorylated P38 and activating transcription factor 2 were obviously increased after overexpressing Noxin, and their expression was downregulated accordingly by transfecting Noxin-small interfering RNA. Moreover, P38 inhibitor counteracted the elevating expression of phosphorylated activating transcription factor 2, Cyclin D1, and Cyclin E1 induced by Noxin overexpression and thereby reversed the effect of Noxin overexpression on facilitating cell growth. Taken together, our studies indicated that Noxin was overexpressed in breast cancer and its positive expression was significantly correlated with advance tumor-node-metastasis stage, positive lymph node metastasis, and poor prognosis. Noxin facilitated the expression of Cyclin D1 and Cyclin E1 through activating P38-activating transcription factor 2 signaling pathway, thus enhanced cell growth of breast cancer.
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http://dx.doi.org/10.1177/1010428317705515DOI Listing
June 2017

WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis.

J Pathol 2017 08 29;242(4):435-447. Epub 2017 Jun 29.

Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, PR China.

The scaffolding protein WWC (WW and C2-domain containing) family is known to regulate cell proliferation and organ size via the Hippo signalling pathway. However, the expression level of WWC3 in human tumours and the mechanisms underlying its role in cellular signal transduction have not yet been reported. Herein, we explored the potential roles of WWC3 in lung cancer cells and the corresponding molecular mechanisms. We found low WWC3 expression in both lung cancer cell lines and lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients with lung cancer. Moreover, the overexpression of WWC3 inhibited the proliferation and invasiveness of lung cancer cells. These effects were mediated by the inhibition and stimulation of the Wnt and Hippo pathways, respectively, in vitro and in vivo. Specifically, WWC3 interacts with Dishevelled (Dvl) proteins, prevents casein kinase 1ϵ from phosphorylating Dvls, and inhibits β-catenin nuclear translocation to inhibit the Wnt pathway. Deleting the WW and C-terminal PDZ-binding domains of WWC3 abrogated these effects. Moreover, the interaction of WWC3 with Dvls reduced the interaction between WWC3 and large tumour suppressor 1 (LATS1), as well as decreasing LATS1 phosphorylation to increase the nuclear importation of yes-associated protein (YAP) and attenuate the Hippo pathway. Deleting the WW domain of WWC3 abrogated this effect. These findings demonstrate the molecular interplay between WWC3, Dvls, and LATS1, and reveal a link between the Wnt and Hippo pathways, which provides a potential target for clinical intervention in lung cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4919DOI Listing
August 2017